The long-term goal is to determine the role of CNS resident cells in the neuropathogenesis of the transmissible spongiform encephalopathies (TSEs), or prion disease. Neurodegenerative changes in the TSEs are similar to those occurring during normal aging, albeit to a lesser degree than in the TSEs and other CNS disease processes. Such as Alzheimer's disease. Deposition of the disease-related prion protein (PrPSc) precedes both activation of microglia and astrocytes, and neuronal damage and loss in TSE diseases. Whether PrPSc is directly toxic to neurons, or indirectly induces neurotoxicity through activation of microglia and astrocytes is unknown. To address the role of local innate immunity in TSE neuropathogenesis we will investigate the development of inflammatory events in TSE-infected brain regions that contain PrPSc but differ in the extent of gliosis and neuropathology. The hypothesis to be investigated is: PrPSc deposition induces chronic glial activation resulting in secretion of soluble factors that mediate or enhance neuronal damage and death. The spatial and temporal pattern of PrPSc deposition, cell activation or loss (e.g., neurons, microglia, and astrocytes), glial secretory products (e.g., cytokines, complement proteins, oxidative metabolites, etc.) and neuropathology (e.g., synaptic density, vacuolar spongiform pathology, cell loss, and apoptosis) will be investigated in the hypoglossal nucleus (a structure that exhibits gliosis, cell loss and vacuolar pathology) and the dorsal root ganglia (a region where no gliosis or overt neuropathology is observed. In vitro studies of microglia and astrocytes co-cultured with PrPSc will investigate the effect(s) of the prion protein on gene expressing and inflammatory mediator secretion by glial cells. These studies will guide additional in vivo damage and loss. Quantitative histological techniques and correlative statistical analysis will establish cause and effect relationships among PrPSc burden, glial activation and secretory products, and neuropathology.